Naphthalimide-based, Single-Chromophore, Emission Ratiometric Fluorescent Sensor for Tracking Intracellular pH.

We report a novel, reversible, cell-permeable, pH-sensor, TRapH. TRapH afforded a pH-sensitive ratiometric emission response in the pH range ~3-6, enabling imaging and quantification of pH in living cells. The biological-applicability of TRapH was illustrated via live-tracking of intracellular pH dynamics in living mammalian cells induced by a synthetic H+-transporter.

An Amphiphilic Peptide Carrier for HCl Transport.

Single molecules that co-transport cations as well as anions across lipid membranes are few despite their high biological utility. The elegant yet simple lipidomimmetic peptide design herein enables efficient HCl transport without the use of any external additives for proton transport. The carboxylic acids in the dipeptide scaffold provide a handle to append two long hydrophobic tails and also provide a polar hydrophilic carboxylate group. The peptide central unit also provides NH sites for anion binding. Protonation of the carboxylate group coupled with the weak halide binding of the terminal NH group results in HCl transport with transport rates of H+ >Cl- . The lipid-like structure also facilitates seamless membrane integration and flipping of the molecule. The biocompatibility, design simplicity, and potential pH regulation of these molecules open up several avenues for their therapeutic use.

Small molecule-derived pH-gated ion transporters.

The pH regulation of transmembrane ion transport is critical for biological processes and has a direct implication on diseases such as cancer. Synthetic transporters that can be regulated using pH show promise as therapeutic agents. This review highlights the importance of the fundamental principles of acid-base chemistry in achieving pH regulation. A systematic classification of transporters based on the pKa of their pH-responsive units aids in correlating the pH regulation of ion transport with the molecular structure. This review also summarises the applications of these transporters and their efficacy in cancer therapy.

Small Peptidic Ionophore for Calcium Transport.

Synthetic calcium transporters are few despite their potential biological significance. Herein, we report small alanine-derived peptides containing pyridyl-triazole motifs for inducing calcium selectivity. The peptides are decorated with hydrophobic alkyl chains to facilitate membrane insertion. The most efficient peptide scaffold has an EC50 value of 0.09 mol % and functions as a calcium carrier.

Ligand Induced CuII Transport Restricts Cancer and Mycobacterial Growth: Towards a Plug-and-Select Ion Channel Scaffold.

Synthetic channels with high ion selectivity are attractive drug targets for diseases involving ion dysregulation. Achieving selective transport of divalent ions is highly challenging due their high hydration energies. A small tripeptide amphiphilic scaffold installed with a pybox ligand selectively transports CuII ions across membranes. The peptide forms stable dimeric pores in the membrane and transports ions by a Cu2+ /H+ antiport mechanism. The ligand-induced excellent CuII selectivity as well as high membrane permeability of the peptide is exploited to promote cancer cell death. The peptide's ability to restrict mycobacterial growth serves as seeds to evolve antibacterial strategies centred on selectively modulating ion homeostasis in pathogens. This simple peptide can potentially function as a universal, yet versatile, scaffold wherein the ion selectivity can be precisely controlled by modifying the ligand at the C terminus.

Quick Access to High-Purity Peptide Drugs Bradykinin, Leuprolide Analogue, 2(PZ-128), and Rapastinel with Minimal Reagents.

Peptide drugs bradykinin, a leuprolide analogue, 2(PZ-128), and rapastinel are synthesized in 56-77% yield using heating-assisted liquid-phase peptide synthesis on a soluble polynorbornene support. These drugs of commercial utility and complex structures are obtained in 2-5.5 h with no epimerization and >95% purity using only 1.2 equivalents of amino acids and coupling reagents. The peptide yield and purity are comparable or superior to the reported methods.

A rink-amide soluble support: high purity conotoxins and other peptides accessed with minimal reagents.

The use of peptides as therapeutics has been growing due to their biocompatibility. Solid phase peptide synthesis typically used to access these peptides requires excess reagents and/or microwave irradiation to drive reactions to completion because the reaction medium is heterogeneous. Reported herein is a soluble polynorbornene support containing rink amide attached sites for synthesizing oligopeptides and conotoxins in high purity using only 1.2 to 2 equivalents of coupling reagents. The support can be isolated as a precipitate from the reaction medium by adding ether. The loading capacity of the support can be easily determined by spectroscopy and can also be tuned by varying the monomer ratio. This support is promising for accessing peptides as the methodology uses minimal reagents and by-products can be easily separated.

Anion-Selective Cholesterol Decorated Macrocyclic Transmembrane Ion Carriers.

Anion transporters play a vital role in cellular processes and their dysregulation leads to a range of diseases such as cystic fibrosis, Bartter's syndrome and epilepsy. Synthetic chloride transporters are known to induce apoptosis in cancer cell lines. Herein, we report triamide macrocycles that are easily synthesized and externally functionalized by pendant membrane-permeable groups. Among a variety of chains appended onto the macrocycle scaffold, cholesterol is found to be the best with an EC50 value of 0.44 µM. The macrocycle is highly anion-selective and transports ions via an OH-/X- antiport mechanism. The macrocycle is an interesting scaffold for ion-transport as it is able to discriminate between various anions and shows a preference for SCN- and Cl-. Such anion-selective transporters are highly attractive model systems to study ion-transport mechanisms and could potentially be of high therapeutic value.

A minimalistic tetrapeptide amphiphile scaffold for transmembrane pores with a preference for sodium.

Synthetic channels or pores that are easy to synthesize, stable and cation-selective are extremely attractive for the development of therapeutics and materials. Herein, we report a pore developed from a small tetrapeptide scaffold that shows a preference for sodium over lithium/potassium. The sodium selectivity is attributed to the appended oligoether tail at the C-terminus. A peptide dimer is proposed as the predominant cation-transporting pore. Such pyridine containing stable pores can be potentially utilized for the pH modulated ion transport.

Triamide macrocyclic chloride receptors via a one-pot tandem reduction-condensation-cyclization reaction.

A pyridine containing triamide macrocycle and its substituted analog have been synthesized in one pot from the corresponding monomer without the use of coupling reagents. The macrocycle can selectively bind chloride ions. The ease of synthesis and chloride-binding properties of the macrocycle make it a highly attractive scaffold for ion-encapsulation, ion-transport and water purification.

Correction: Triamide macrocyclic chloride receptors via a one-pot tandem reduction-condensation-cyclization reaction.

Correction for 'Triamide macrocyclic chloride receptors via a one-pot tandem reduction-condensation-cyclization reaction' by Harekrushna Behera, et al., Org. Biomol. Chem., 2017, DOI: .

Cation-halide transport through peptide pores containing aminopicolinic acid.

Synthetic pores that selectively transport ions of biological significance through membranes could be potentially used in medical diagnostics or therapeutics. Herein, we report cation-selective octapeptide pores derived from alanine and aminopicolinic acid. The ion transport mechanism through the pores has been established to be a cation-chloride symport. The cation-chloride co-transport is biologically essential for the efficient functioning of the central nervous system and has been implicated in diseases such as epilepsy. The pores formed in synthetic lipid bilayers do not exhibit any closing events. The ease of synthesis as well as infinite lifetimes of these pores provides scope for modifying their transport behaviour to develop sensors.

Cation-Transporting Peptides: Scaffolds for Functionalized Pores?

Protein pores that selectively transport ions across membranes are among nature's most efficient machines. The selectivity of these pores can be exploited for ion sensing and water purification. Since it is difficult to reconstitute membrane proteins in their active form for practical applications it is desirable to develop robust synthetic compounds that selectively transport ions across cell membranes. One can envision tuning the selectivity of pores by incorporating functional groups inside the pore. Readily accessible octapeptides containing (aminomethyl)benzoic acid and alanine are reported here that preferentially transport cations over halides across the lipid bilayer. Ion transport is hypothesized through pores formed by stable assemblies of the peptides. The aromatic ring(s) appear to be proximal to the pore and could be potentially utilized for functionalizing the pore interior.

Aminobenzoic acid incorporated octapeptides for cation transport.

Robust oligopeptides that mimic natural ion channels are attractive for use as molecular switches or model systems to study ion transport. Herein, we report octapeptides derived from aminobenzoic acid and l/d amino acids. Two of the alanine containing peptides were found to be most active and the peptide containing p-aminobenzoic acid was found to be most active (2.4 times its m-analog). Experimental studies indicate the peptides do not transport halides and transport alkali metal ions.

Soluble non-cross-linked poly(norbornene) supports for peptide synthesis with minimal reagents.

Solid-phase peptide synthesis has been an attractive method for synthesizing peptides because it is quick and can be automated. The heterogeneous reaction medium in solid-phase peptide synthesis necessitates the use of large equivalents of reagents to drive the reactions to completion. Peptide synthesis using soluble, yet isolable, supports is an attractive alternative to solid-phase peptide synthesis. Reported herein is a soluble poly(norbornene)-derived support containing multiple attachment sites for high loading capacities and solubilizing oligoether/alkyl groups. The Ala-attached support has been used to synthesize tri- to octapeptides in 28 to 97% yields using only 1.2 equiv of amino acids and coupling reagents. The acyclic hexapeptide precursor to natural product segatalin A was synthesized in 41% yield on the support using one-eighth of the equivalents of coupling reagents compared to that in reported procedures. The support could be recovered in up to 98% yield after peptide synthesis, and the recovered support was utilized to synthesize tri- and tetrapeptides that contain amino acids other than Ala at the C-terminus in ca. 80% yields.

Hydrophobic cyclic dipeptides as M+/Cl- carriers.

Transmembrane ion-pair co-transport using synthetic transporters is non-trivial. Herein, cyclic dipeptide ion-carriers with dangling ester motifs to bind cations and amide-NH to bind anions are reported. The pendant lipophilic norbornene units aid in membrane insertion to achieve MCl co-transport with this simple design.

Macrocyclic Transmembrane Anion Transporters via a One-Pot Condensation Reaction.

Synthetic chloride transporters are potential therapeutic agents for cystic fibrosis and cancer. Reported herein are macrocyclic transmembrane chloride transporters prepared by a one-pot condensation reaction. The most efficient macrocycle possesses a fine balance of hydrophobicity for membrane permeation and hydrophilicity for ion recognition. The macrocycle transports chloride ions by forming channels in the membrane. Hydrogen bonds and anion-π interactions assist chloride transport.

Rational approach to polymer-supported catalysts: synergy between catalytic reaction mechanism and polymer design.

Supported catalysis is emerging as a cornerstone of transition metal catalysis, as environmental awareness necessitates "green" methodologies and transition metal resources become scarcer and more expensive. Although these supported systems are quite useful, especially in their capacity for transition metal catalyst recycling and recovery, higher activity and selectivity have been elusive compared with nonsupported catalysts. This Account describes recent developments in polymer-supported metal-salen complexes, which often surpass nonsupported analogues in catalytic activity and selectivity, demonstrating the effectiveness of a systematic, logical approach to designing supported catalysts from a detailed understanding of the catalytic reaction mechanism. Over the past few decades, a large number of transition metal complex catalysts have been supported on a variety of materials ranging from polymers to mesoporous silica. In particular, soluble polymer supports are advantageous because of the development of controlled and living polymerization methods that are tolerant to a wide variety of functional groups, including controlled radical polymerizations and ring-opening metathesis polymerization. These methods allow for tuning the density and structure of the catalyst sites along the polymer chain, thereby enabling the development of structure-property relationships between a catalyst and its polymer support. The fine-tuning of the catalyst-support interface, in combination with a detailed understanding of catalytic reaction mechanisms, not only permits the generation of reusable and recyclable polymer-supported catalysts but also facilitates the design and realization of supported catalysts that are significantly more active and selective than their nonsupported counterparts. These superior supported catalysts are accessible through the optimization of four basic variables in their design: (i) polymer backbone rigidity, (ii) the nature of the linker, (iii) catalyst site density, and (iv) the nature of the catalyst attachment. Herein, we describe the design of polymer supports tuned to enhance the catalytic activity or decrease, or even eliminate, decomposition pathways of salen-based transition metal catalysts that follow either a monometallic or a bimetallic reaction mechanism. These findings result in the creation of some of the most active and selective salen catalysts in the literature.

Macrocyclic cyclooctene-supported AlCl-salen catalysts for conjugated addition reactions: effect of linker and support structure on catalysis.

AlCl-salen (salen=N,N'-bis(salicylidene)ethylenediamine dianion) catalysts supported onto macrocyclic oligomeric cyclooctene through linkers of varying length and flexibility have been developed to demonstrate the importance of support architecture on catalyst activity. The role played by the support and the linkers in dictating catalyst activity was found to vary for reactions with contrasting mechanisms, such as the bimetallic cyanide and the monometallic indole addition reactions. While the flexible support significantly enhanced the cyanide addition reaction, most likely by improving salen-salen interactions in the transition state, it lowered the reaction rate for the monometallic indole reaction. For both reactions, significant increase in catalytic activity was observed for catalysts with the longest linkers. The effect of the flexible macrocyclic support on catalysis was further exemplified by the enhanced activity of the supported catalyst in comparison with its unsupported analogue for the conjugate addition of tetrazoles, which is known to be catalyzed by dimeric mu-oxo-salen catalysts. Our studies with the cyclooctene supported AlCl-salen catalysts provides significant insights for rationally designing highly efficient AlCl-salen catalysts for a diverse set of reactions.

Synthesis and photocleavage of a new dimeric bis(o-nitrobenzyl) diether tether.

A new photocleavable linker, 4,4'-bis(alkoxymethyl-3,3'-dinitro)biphenyl, is reported that undergoes photolysis at two positions to release two equivalents of primary, secondary, or benzylic alcohol in yields that are higher than those obtained from the analogous monomeric o-nitrobenzyl ethers.